Biology subjects

Hovhannisyan, L.

Publications and source records attributed to Hovhannisyan, L..

3 recordsLinked to original sources

bioRxiv2023

HPV and p53 status as precision determinants of head and neck cancer response to DNA-PKcs inhibition in combination with irradiation

Major risk factors of head and neck squamous cell carcinoma (HNSCC) are tobacco use and human papillomavirus (HPV). HPV E6 oncoprotein leads to the degradation of the p53 protein, whereas HPV-negative cancers are frequently associated with TP53 mutations. Peposertib is a potent and selective, orally administered small-molecule inhibitor of the catalytic subunit of the DNA-dependent kinase (DNA-PKcs), a key regulator of non-homologous end joining (NHEJ). NHEJ inhibition along with irradiation (IR)-induced DNA double-strand breaks has the potential to increase antitumor treatment efficacy. Here, we investigated the responses of HNSCC models with distinct HPV and p53 status to treatments with IR, DNA-PKcs inhibition, and their combination. We observed that IR-induced DNA damage combined with peposertib administration shortly before IR results in decreased cell viability and proliferation and causes DNA repair delay in all the studied HNSCC cell lines. However, our data confirm that the actual cell fate upon this treatment is strongly dependent on cellular p53/HPV status. Cells lacking functional p53 due to its degradation by HPV or due to the presence of a loss-of-function mutation are arrested in the G2 phase of the cell cycle and eliminated by apoptosis whereas p53-proficient HNSCC cell lines undergo senescence. Consequently, HPV+ cancer cell lines and xenografts display stronger and more durable responses and seem to benefit from the combined treatment more than p53-proficient HNSCCs. In conclusion, DNA-PKcs inhibitor peposertib should be further studied as a potential radiosensitizer for HNSCCs, taking into consideration the genetic background and the HPV status of a particular tumor.

cancer biology↗

bioRxiv2023

Characterization of predictive power of extracellular signal recordings in a cerebral ischemia animal model

IntroductionGlobal cerebral ischemia leads to substantial and irreversible damage of brain tissue. As it progresses in a less severe course, certain strategies should be implemented to screen this condition on its early onset. The research aimed to characterize the local field potential (LFP) alterations recorded during the subacute phase of the cerebral ischemia animal model and provide their predictive power. MethodsThe extracellular signal recordings from the parietal cortex of animals were registered with a neural probe. The signal was amplified, filtered, digitized, and acquired with Intan amplifier and USB interface boards. The recordings were obtained both in normal conditions and after implementation of unilateral common carotid artery occlusion. The data analysis and classification were performed using NI Diadem software and custom-written code in IPython environment. The respective morphological changes were screened in cerebral cortex and hippocampus. The whole-brain slicing and TTC staining were used for infarct size evaluation. ResultsIn Fourier spectrograms of intact brain recordings, a peak at 14.4-15 Hz frequencies was detected, whereas this phenomenon was absent in cerebral ischemia model recordings. In channels cross-correlograms for intact and ischemic brain recordings, there was a clear difference detected in the maximum peak power. With autocorrelation analysis, the long lag rhythmicity was detected in normal brain recordings, while no rhythmicity was observed in ischemic brains. The morphological and behavioral analyses did not result in any significant changes and neural loss. The TTC staining failed to show any damaged area ipsilateral to the occluded common carotid artery. ConclusionWe have analyzed and described the major characteristics of the electrical activity that vary between neural populations of the parietal cortex of normal and ischemic brains. This data proves that LFP recordings can be used for further investigation of changes occurring in the subacute phase after unilateral common carotid artery occlusion.

neuroscience↗

bioRxiv2021

Tumour mutations in long noncoding RNAs that enhance cell fitness

Long noncoding RNAs (lncRNAs) can act as tumour suppressors or oncogenes to repress/promote tumour cell proliferation via RNA-dependent mechanisms. Recently, genome sequencing has identified elevated densities of tumour somatic single nucleotide variants (SNVs) in lncRNA genes. However, this has been attributed to phenotypically-neutral "passenger" processes, and the existence of positively-selected fitness-altering "driver" SNVs acting via lncRNAs has not been addressed. We developed and used ExInAtor2, an improved driver-discovery pipeline, to map pancancer and cancer-specific mutated lncRNAs across an extensive cohort of 2583 primary and 3527 metastatic tumours. The 54 resulting lncRNAs are mostly linked to cancer for the first time. Their significance is supported by a range of clinical and genomic evidence, and display oncogenic potential when experimentally expressed in matched tumour models. Our results revealed a striking SNV hotspot in the iconic NEAT1 oncogene, which was ascribed by previous studies to passenger processes. To directly evaluate the functional significance of NEAT1 SNVs, we used in cellulo mutagenesis to introduce tumour-like mutations in the gene and observed a consequent increase in cell proliferation in both transformed and normal backgrounds. Mechanistic analyses revealed that SNVs alter NEAT1 ribonucleoprotein assembly and boost subnuclear paraspeckles. This is the first experimental evidence that mutated lncRNAs can contribute to the pathological fitness of tumour cells.

genomics↗